Abstract: The hypothalamic-pituitary-gonadal (HPG) axis regulates the timing of pubertal onset. Premature re-activation of gonadotropin-releasing hormone (GnRH) secretion in childhood leads to development of central precocious puberty (CPP). CPP, in addition to conferring behavioral and psychiatric disorders, is associated with increased risk of cardiovascular and cardiometabolic disease, obesity, diabetes, and cancer in adulthood. Therefore, there is a dire need to identify the pathways that are involved in early re-activation of the HPG axis to better diagnose and treat this disorder. Studies have identified the central roles of KISS1 and KISS1R in activation of the HPG axis. More recently, we have identified mutations in the imprinted genes, MKRN3 and DLK1, in familial CPP, suggesting that both genetic and epigenetic alterations regulate the timing of puberty. We now propose to use a population genetics approach to perform an integrated analysis of genetic and epigenetic variants to identify new underlying causes for CPP in individuals with no known causes. The objective of our study is to investigate the association between copy number variants and DNA methylation in patients with idiopathic CPP. We will address this objective in two aims: 1) perform association analysis between genetic alterations and DNA methylation in a cohort of patients with CPP; and 2) validate the associations identified using a second cohort of patients and further determine if the regions associated with DNA methylation are enriched for regulatory elements as defined by the Encyclopedia of DNA Elements (ENCODE) consortium. This proposed analysis will help to delineate correlated genetic and epigenetic alterations underlying CPP. The results will aid in the development of new diagnostic strategies for CPP and facilitate timely intervention and treatment to improve the health and quality of life for these children.